E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary Arterial Hypertension |
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E.1.1.1 | Medical condition in easily understood language |
Elevated blood pressure in blood vessels in the lungs. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of macitentan on right ventricular and hemodynamic properties in patients with symptomatic PAH. |
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E.2.2 | Secondary objectives of the trial |
Secondary objective:
To evaluate the safety and tolerability of macitentan in patients with symptomatic PAH
Exploratory objectives:
To investigate the effect of macitentan on disease-related circulating biomarkers in patients with symptomatic PAH
To explore a potential association between change in right ventricular properties and clinical outcome in patients with symptomatic PAH
To investigate the effect of macitentan on ventriculo-arterial coupling in patients with symptomatic PAH
To evaluate the effect of macitentan on left ventricular properties in patients with symptomatic PAH |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Three sub-studies are planned and described under the same protocol:
1. Metabolism sub-study, in the US only
Objectives: To assess the effect of macitentan on cardiac and arterial metabolism in patients with symptomatic pulmonary arterial hypertension by Positron Emission Tomography (PET) -Magnetic Resonance (MR) imaging.
To further investigate the effect of macitentan on right ventricular function in patients with symptomatic pulmonary arterial hypertension.
2. Biopsy sub-study
Objectives: To assess the histological and biochemical effects of macitentan on the endomyocardium of the interventricular septum in patients with symptomatic pulmonary arterial hypertension.
To assess the biochemical effects of macitentan on peripheral blood mononuclear cells (PBMC) in patients with symptomatic pulmonary arterial hypertension.
3. Echo sub-study
Objective: To assess the effect of macitentan on right and left ventricular function by echocardiography in patients with symptomatic pulmonary arterial hypertension. |
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E.3 | Principal inclusion criteria |
The full list of inclusion criteria is provided in Section 4.3 of the Protocol and all patients must fulfill all criteria. The main inclusion criteria are:
1. Signed informed consent prior to any study-mandated procedure
2. Symptomatic pulmonary arterial hypertension (PAH)
3. World Health Organization (WHO) Functional Class (FC) III
4. PAH etiology belonging to one of the following groups according to Nice classification:
1.1 Idiopathic PAH
1.2 Heritable PAH
1.3 Drug- and toxin-induced PAH
1.4.1 PAH associated with connective tissue disease
1.4.4 PAH associated with congenital heart diseases: only simple (atrial septal defect, ventricular septal defect, patent ductus arteriosus) congenital systemic to pulmonary shunts at least 2 year post surgical repair
5. Hemodynamic diagnosis of PAH confirmed by right heart catheterization (RHC) performed between Day −28 and Day 1 (inclusion RHC; RHC data obtained at study site within this time frame, prior to obtaining signed informed consent, are acceptable) showing:
• mPAP ≥ 25 mmHg and
- PCWP or LVEDP ≤ 12 mmHg and PVR ≥ 4 Wood Units (WU) (320 dyn.sec.cm-5) or
- 12 mmHg ≤ PCWP or LVEDP ≤ 15 mmHg and PVR ≥ 6WU (480 dyn.sec.cm-5)
- 6.6-minute walk distance (6MWD) ≥ 150 m during screening
7. For patients treated with oral loop diuretics, treatment dose must be stable since at least 1 month prior to the inclusion RHC
8. For patients treated with PDE-5 inhibitors, treatment dose must be stable since at least 3 months prior to the inclusion RHC (initiation of PDE-5 inhibitors during screening is allowed after all screening assessments have been performed).
9. For patients treated with beta blockers, treatment dose must be stable since at least 1 month prior to the inclusion RHC
10. Men or women ≥18 and < 75 years. For patients aged ≥ 65 and < 75 years, an eligibility form will be submitted to a Steering Committee member who will reserve the right to exclude the patient.
11. Women of childbearing potential must:
a. Have a negative serum pregnancy test during screening and a negative urine pregnancy test on Day 1, and
b. Agree to use reliable methods of contraception from screening up to 30 days after study treatment discontinuation, and
c. Agree to perform monthly pregnancy tests up to 30 days after study treatment discontinuation |
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E.4 | Principal exclusion criteria |
The full list of exclusion criteria is provided in Section 4.4 of the Protocol and all patients must not fulfill any exclusion criterion. The main exclusion criteria are:
1. Body weight < 40 kg
2. Body mass index (BMI) > 35kg/m2. For patients with 30kg/m2 < BMI < 35kg/m2, an eligibility form will be submitted to a Steering Committee member who will reserve the right to exclude the patient.
3. Pregnancy, breastfeeding or intention to become pregnant during the study
4. Recently started (< 8 weeks prior to informed consent signature) or planned cardio-pulmonary rehabilitation program
5. Known concomitant life-threatening disease with a life expectancy < 12 months
6. Any condition likely to affect protocol or treatment compliance
7. Hospitalization for PAH (except for diagnosis of PAH) within 3 months prior to informed consent signature
8. Left atrial volume indexed for body surface area (BSA) ≥ 43mL/m2 by echocardiography or cardiac MRI
9. Moderate to severe left-heart valvular disease
10. History of pulmonary embolism or deep vein thrombosis
11. Presence of one or more of the following signs of relevant lung disease at any time up to screening:
- Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% of predicted (eligible only if no or mild interstitial lung disease on computed tomography).
- FVC < 60% of predicted.
- Forced expiratory volume in one second (FEV1) < 60% of predicted.
12. Moderate to severe restrictive lung disease (i.e., total lung capacity < 60% of predicted value) at any time prior to enrollment.
13. Historical evidence of significant coronary artery disease established by:
• History of myocardial infarction or
• More than 50% stenosis in a coronary artery (by percutaneous coronary intervention or angiography) or
• Elevation of the ST segment on electrocardiogram or
• History of coronary artery bypass grafting or
• Stable angina
14. Known uncontrolled diabetes mellitus (in the opinion of the investigator)
15. Severe renal insufficiency (calculated creatinine clearance < 30 mL/min)
16. Cancer
17. Systolic blood pressure < 90 mmHg
18. Severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin > 3 × ULN accompanied by an AST elevation > ULN at Screening.
19. Hemoglobin < 100g/L
20. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of the normal range
21. Need for dialysis
22. Responders to acute vasoreactivity test based on medical history
23. Prior use of endothelin receptor antagonists, stimulators of soluble guanylate cyclase or prostacyclin or prostacyclin analogues
24. Treatment with strong inducers of CYP3A4 within 4 weeks prior to study treatment initiation (e.g., carbamazepine, rifampicin, rifabutin, phenytoin and St. John’s Wort)
25. Treatment with strong inhibitors of CYP3A4 within 4 weeks prior to study treatment initiation (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir)
26. Treatment with another investigational drug (planned, or taken within the 3 months prior to study treatment initiation).
27. Hypersensitivity to any endothelin receptor antagonist or any excipients of the formulation of macitentan (lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, polyvinyl alcohol, polysorbate, titanium dioxide, talc, xanthan gum, and lecithin soya)
28. Claustrophobia
29. MRI-incompatible permanent cardiac pacemaker, automatic internal cardioverter
30. Metallic implant (e.g., defibrillator, neurostimulator, hearing aid, permanent use of infusion device)
31. Atrial fibrillation, multiple premature ventricular or atrial contractions (PVCs/PACs), or any other condition that would interfere with proper cardiac gating during magnetic resonance imaging (MRI)
32. For patients enrolling in the metabolism sub-study only: glucose intolerance
33. For patients enrolling in the biopsy sub-study only: PAH etiology belonging to Nice classification 1.4.4: PAH associated with congenital heart diseases or 1.4.1: PAH associated with connective tissue disease |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy endpoint
The study has two primary efficacy endpoints:
-Change from baseline to Week 26 in Right Ventricular (RV) Stroke Volume (RVSV) assessed by cardiac MRI from pulmonary artery flow.
-Ratio of Week 26 to baseline Pulmonary Vascular Resistance (PVR) assessed by RHC.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints
Change from baseline to Week 26 in:
-RV End Diastolic Volume (RVEDV)
-RV End Systolic Volume (RVESV)
-RV Ejection Fraction (RVEF)
-RV mass
-six-minute walk distance (6MWD)
-World Health Organization (WHO) Functional Class (FC) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
France |
Germany |
Hong Kong |
Israel |
Italy |
Malaysia |
Netherlands |
Russian Federation |
Singapore |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS
An interim analysis will be conducted when 42 patients have available assessment data for both primary endpoints. If the interim analysis concludes that the study is positive on both primary endpoints, enrollment may stop. Otherwise, the study will continue until 100 patients are enrolled. The decision to stop or continue the study will be taken jointly by the Steering Committee and the sponsor, considering statistical analysis results as well as clinical expertise. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |